Survival as it relates to p16 overexpression and MIB-1 (Ki-67) proliferation in primary squamous cell vaginal carcinoma was studied.Retrospective chart review from 1997 to 2006 revealed 43 patients who were treated for primary vaginal cancer at Emory University hospitals. Tissue was evaluated by immunohistochemical staining for the presence of p16 and MIB-1 markers, and survival data were examined.Patients who had primary squamous cell vaginal cancers (n = 31) with a positive diffuse staining of p16 had significantly (P = .003) improved survival (~49.5 months) compared with p16-negative patients (~25.3 months). Stage-specific analysis with 30 additional reported cases showed a significant survival benefit for p16-positive vaginal cancers compared with p16-negative cancers for stages I and II (P = .017; hazard ratio [HR] 0.400; 95% confidence interval [CI], 0.189-0.850) and stages III and IV (P = .001; HR, 0.176; 95% CI, 0.066-0.479). No difference was observed in survival for MIB-1-positive tumors (P = .984; HR, 1.008; 95% CI, 0.483-2.104).The p16 marker has a significant prognostic impact in primary squamous cell vaginal cancers across all tumor stages.